Interictal discharge events: from physiological effects to cognitive consequences. Many epileptic subjects are more likely to show learning disabilities, perform less well than peers at school and have a lower distribution of IQ scores. Additionally, many epileptic subjects suffer from important co-morbidities that often lead to learning impairments including autistic spectrum disorder, mood disorders, sleep disorders and psychosis. Recently, in addition to seizure events themselves, attention has been devoted to the interictal discharge events prevalent in a large fraction of epileptic subjects. Between seizure events, intracranial field potential recordings in epilepsy subjects are often characterized by internal stimulation events denominated interictal discharge events (IIDEs). Our proposal aims to understand how the neuronal circuits in the medial temporal lobe (MTL) responsible for learning are affected by clinical and subclinical manifestations of epilepsy. Converging evidence from neurology, electrophysiology, imaging, electrical stimulation and molecular studies point to the prominent role of the hippocampus and related MTL structures in learning. Our proposal is based on a collaborative effort between four PIs with extensive experience in working with epileptic patients (Kreiman, Ph.D., Anderson, M.D., Ph.D., Loddenkemper, M.D. and Madsen, M.D.). We study patients with intractable epilepsy implanted with electrodes to localize epileptogenic areas for resection. Preventing adverse effects in this procedure requires understanding the physiological and behavioral functions of the epileptogenic areas. Thus, in addition to addressing key questions about learning, our work may directly benefit those patients undergoing surgical treatment. Our electrophysiological recordings provide us with a unique opportunity to examine the human MTL circuitry at high spatial and temporal resolution. Although it has been proposed that IIDEs may play an important role in the cognitive deficits observed in several epileptic patients, the link between IIDEs and cognition remains only poorly understood. The goal of this proposal is to further our understanding of the physiological changes evoked by IIDEs and their consequent roles in cognitive function. We hypothesize, with others, that IIDEs in medial temporal lobe areas including the hippocampus and surrounding structures play an important role in the cognitive impairments prevalent in epileptic subjects. We will test the hypothesis that IIDEs influence learning performance and physiological responses in the temporal lobe. We will further assess the spatial and temporal specificity of potential modulatory or disruptive effects by IIDEs. The goals of this proposal aim to test this hypothesis by combining physiological, computational and behavioral tools. The specific aims are: 2.1 Specific Aim 1: Characterize the effects of interictal discharge events on physiological activity 2.2 Specific Aim 2: Evaluate the effects of interictal discharge events on cognition PUBLIC HEALTH RELEVANCE: Interictal discharge events: from physiological effects to cognitive consequences Children with epilepsy show learning disabilities and perform less well than peers at school. The prevention and treatment of the co-morbidities associated with epilepsy is an urgent theme of brain research. We aim to understand how clinical and subclinical manifestations of epilepsy affect the neuronal circuits responsible for learning and memory formation. Our team includes neurologists, neurosurgeons and cognitive neuroscientists and combines physiological, computational and cognitive techniques to help address the cognitive challenges in subjects with epilepsy.